Glutamine is the most abundant plasma amino acid and is involved in many growth promoting pathways. In particular, glutamine is involved in oxidation in the TCA cycle and in maintaining cell redox equilibrium, and also provides nitrogen for nucleotide and amino acid synthesis (Curi et al., Front. Biosc. 2007, 12, 344-57; DeBardinis and Cheng, Oncogene 2009, 313-324). Many cancer cells rely on glutamine metabolism as a consequence of metabolic changes in the cell, including the Warburg effect where glycolytic pyruvate is converted to lactic acid rather than being used to create Acetyl CoA (Koppenol et al., Nature Reviews 2011, 11, 325-337). As a consequence of this reliance on glutamine metabolism, such cancer cells are sensitive to changes in exogenous glutamine levels. Furthermore, there is much evidence to suggest that glutaminolysis plays a key role in certain cancer types (Hensley et al., J. Clin. Invest. 2013, 123, 3678-3684), and is associated with known oncogenic drivers such as Myc (Dang, Cancer Res. 2010, 70, 859-863).
The first step of glutamine catabolism to glutamate is catalysed by glutaminase, which exists as 2 isoforms GLS1 and GLS2, originally identified as being expressed in the Kidney and Liver respectively. Kidney glutaminase (GLS1) is known to be more ubiquitously expressed than Liver glutaminase (GLS2), and has 2 splice variants, KGA and the shorter GAC isoform, both of which are located in the mitochondria. (Elgadi et al., Physiol. Genomics 1999, 1, 51-62; Cassago et al., Proc. Natl. Acad. Sci. 2012, 109, 1092-1097). GLS1 expression is associated with tumour growth and malignancy in a number of disease types (Wang et al., Cancer Cell 2010, 18, 207-219; van der Heuval et al., Cancer Bio. Ther. 2012, 13, 1185-1194). Inhibitors of GLS1 are therefore expected to be useful in the treatment of cancer, as monotherapy or in combination with other anti-cancer agents.